Perhexiline, a "metabolic" anti-anginal agent currently under investigation in management of congestive heart failure and acute coronary syndromes improves platelet nitric oxide responsiveness in patients with impaired responsiveness. The current study investigated possible interactions between perhexiline and the nitric oxide donor nitroglycerin on arterial stiffness, neutrophil superoxide release and on platelet nitric oxide responsiveness. Patients (n=39) with stable angina pectoris, awaiting cardiac catheterization were randomized to additional perhexiline or unchanged drug therapy; all patients received nitroglycerin infusion for 2 h. Vasomotor responses to perhexiline and combined perhexiline/nitroglycerin were examined using changes in augmentation index, measured via applanation tonometry. Neutrophil superoxide release was measured ex vivo utilizing lucigenin mediated chemiluminescence and effect of perhexiline on inhibition of platelet aggregation by sodium nitroprusside was also measured. Perhexiline alone did not affect augmentation index, neutrophil superoxide release, or ex vivo platelet sodium nitroprusside response. Nitroglycerin decreased augmentation index (P<0.01) and superoxide release (P<0.05). Magnitude of inhibition of superoxide release was significantly enhanced by perhexiline pre-treatment (P<0.05); however perhexiline had no effect on magnitude of vasomotor response to nitroglycerin. In conclusion, perhexiline exerts no effects on arterial stiffness and does not potentiate nitroglycerin induced dilatation. In patients with normal platelet function perhexiline does not affect platelet nitric oxide responsiveness. In vivo low dose nitroglycerin inhibits neutrophil superoxide release; this effect is potentiated by pre-treatment with perhexiline. These "anti-inflammatory" effects of nitroglycerin may contribute to utility in acute coronary syndromes and congestive heart failure.
Liberts, E., Willoughby, S. R., Kennedy, J. A., & Horowitz, J. D. (2007). Effects of perhexiline and nitroglycerin on vascular, neutrophil and platelet function in patients with stable angina pectoris. European Journal of Pharmacology, 560(1), 49-55. https://doi.org/10.1016/j.ejphar.2007.01.001